This editorial summarizes results from a comprehensive systematic review and meta-analysis, the largest to date, of all placebo-controlled randomized clinical trials (RCTs) on the effect of testosterone therapy on cardiovascular-related problems.10

This analysis, performed on the largest number of studies collected so far, indicates that testosterone therapy is not related to any increase in cardiovascular risk.

Present data do not support a causal role between testosterone therapy and cardiovascular events.

In studies performed in subjects with metabolic derangements a protective effect of testosterone therapy on cardiovascular risk was observed.

Testosterone therapy in hypogonadal men can be a valuable strategy to improve metabolic profile, reduce body fat and increase lean muscle mass, which would ultimately reduce the risk of heart disease.

No sponsorship bias was detected, because no difference in MACE risk was found when the analysis was performed according to the presence or absence of drug company financing.

This new systematic review and meta-analysis of randomized controlled trials reporting the effects of testosterone therapy on different cardiovascular outcomes, included 75 RCTs with a total of 3016 patients on testosterone therapy and 2448 patients on placebo, for mean duration of 34 weeks.

The principal outcome of this analysis was the effect of testosterone therapy, as compared with placebo, on the incidence of new major adverse cardiovascular events (MACE). MACE was defined as the composite of cardiovascular death, non-fatal acute myocardial infarction and stroke, and acute coronary syndromes and/or heart failure reported as serious adverse events. This was done to comply with requirements for drug safety assessment, as required by regulatory agencies.

Testosterone was administered in different doses, formulations (oral, intramuscular and transdermal testosterone preparations) and in mixed populations of hypogonadal/eugonadal subjects.

What is known

The notion that testosterone is "bad for the heart" arose from the well documented simple observation that heart diseases are more prevalent in men than in women.11-18 Acute coronary heart disease and ischaemic stroke events appears approximately 10 years earlier in men than in women, and these rates remain higher in men than in women in all age groups.11 More men are living with and dying of coronary heart disease than women, and have more hospital discharges for cardiovascular diseases.19 These observations contributed to the perception that heart disease is a “man’s disease”.19

Because men have higher testosterone, it was automatically assumed that testosterone may be the culprit. Further support for this notion comes from case reports of sudden cardiovascular death amongst male athletes abusing anabolic steroids (which are synthetic compounds similar to testosterone)20-24, and observations that testosterone dose-dependently increases hematocrit25,26 and reduces HDL-cholesterol at supra-physiologically high levels.27-29

However, longitudinal studies which follow large populations of men for many years demonstrate that it is reduced, rather than increased testosterone levels, which are associated with elevated risk of cardiovascular disease, cardiovascular mortality and all-cause mortality.30,31 This can be explained by the well documented strong associations of hypogonadism with a number of cardiovascular risk factors, including adiposity and increased waist circumference, insulin resistance and type 2 diabetes, high blood pressure and inflammation.32-37

What this study adds

The results from the comprehensive systematic review and meta-analysis presented here show that testosterone therapy is not related to any increase in cardiovascular risk, and that it may have a protective effect on cardiovascular risk in men with metabolic derangements.10 This conclusion is based on an analysis of the largest number of studies collected so far, which clearly refutes the previously purported causal role between testosterone therapy and cardiovascular events.

A strength of this meta-analysis is that its principal outcome was the effect of testosterone therapy, as compared with placebo, on the incidence of new major adverse cardiovascular events (MACE).10 A previous meta-analysis, which concluded that testosterone therapy increased the risk of cardiovascular-related events38, included many events which are not typically considered for the assessment of cardiovascular risk (e.g., peripheral edema, self-reported syncope etc.). This can be grossly misleading due to the limited reliability of diagnostic criteria used to attribute these events as drug-related. It should be recognized that the use of MACE, instead of a broader ambiguous definition of cardiovascular side effects, has the advantage of a clearer diagnostic definition and precise diagnosis, which is less dependent on investigators’ subjective opinions. Therefore, the assessments of cardiovascular safety of any therapy should be based on the incidence of MACE, which are easier to detect and less controversial in diagnosis. It should be underscored that regulatory agencies assessing the safety of drugs require analyses of MACE and not of broadly defined cardiovascular side effects.39

This meta-analysis also did not observe any sponsorship bias, because no difference in cardiovascular risk was found when the analysis was performed according to the presence or absence of drug company funding.10 This is also in contrast to the meta-analysis just mentioned, which reported that the effects of testosterone on cardiovascular-related events varied with source of funding.38

Supporting data from other studies

Multiple other lines of evidence concur with the conclusions in this meta-analysis. Two notable studies demonstrated that testosterone therapy decreases mortality compared with no testosterone treatment40, and improves survival in hypogonadal men with type 2 diabetes.41 Further support comes from The MrOS (Osteoporotic Fractures in Men) study which after a 5-year follow-up found that an apparent threshold of over 550 ng/dL (approximately 19 nmol/L) needs to be reached in order to reduce risk of cardiovascular events.42 In this study, men in the group with highest testosterone level over 550 ng/dL had a 30% lower risk of cardiovascular events compared with men with testosterone levels below 550 ng/dL, where no protective effect was noted.42 This association remained after adjustment for traditional cardiovascular risk factors and was not changed in analyses excluding men with known cardiovascular disease at.42

Reflections

A few flawed studies of epidemiological observations induced an epidemic of sensational and misleading media coverage and false claims alleging potential dangerous effect of testosterone therapy on the cardiovascular system.43,44 Over the past year popular press headlines have purported that testosterone therapy is associated with serious cardiac hazards. However, as outlined here, meta-analysis of the largest number of studies collected to date shows that testosterone therapy does not increase cardiovascular events, and to the contrary, that it is protective against cardiovascular events in hypogonadal men.10

According to expert opinion, testosterone therapy in hypogonadal men can be a valuable strategy to improve metabolic profile, reduce body fat and increase lean muscle mass, which would ultimately reduce the risk of heart disease.10